Motilin, erythromycin, and the gastric migrating motor complex: site of action

Motilin is a putative hormone which induces a premature migrating motor complex when administered exogenously, but the target organ for this hormonal effect is undetermined. Our aim was to determine whether motilin and the motilin agonist, erythromycin, induce a premature migrating motor complex via an effect directly on the stomach. Six dogs underwent splenectomy and ligation of all branches of the splenic artery except the left gastroepiploic and short gastric arteries to the proximal stomach. An intra-arterial catheter was placed in the proximal splenic artery for close intra-arterial injection of motilin and erythromycin directly to the gastric corpus/proximal antrum. After recovery, the minimum effective dose required to induce a premature migrating motor complex was determined for motilin and for erythromycin given close intra-arterially or intravenously (systemically) by monitoring upper gut myoelectric activity. Minimum effective doses of motilin and erythromycin were the same whether given intra-arterially or intravenously. The latency interval or the time to onset of a premature Phase III was less than 2 minutes for intra-arterial or intravenous administration (P > 0.05). The characteristics of induced-Phase HI activity (appearance, duration, velocity) did not differ from spontaneous Phase HI activity (P > 0.05). Although plasma motilin concentrations increased after threshold doses of both motilin and erythromycin, increases in plasma motilin occurred later after erythromycin (lOmin) than after exogenous motilin (3 min). Our findings suggest that motilin initiation of the migrating motor complex does not occur by independent stimulation of putative receptors in the gastric corpus or proximal antrum.     

Sham feeding disrupts phase III of the duodenal migrating motor complex in humans

The role of the vagus nerve in the control of the intestinal migrating motor complex (MMC) is unclear. This study aimed to evaluate the effect of physiological vagal stimulation with sham feeding on phase III of the MMC. Antroduodenal motility was recorded in six healthy volunteers. The first phase III was used as a control, and sham feeding was performed during the second phase III. The MMC was disrupted within 1.5 ± 0.4 min of sham feeding and its duration was shorter than the control phase III. Phase III propagation was inhibited in all subjects, most of them exhibiting no propagation beyond the third duodenal recording site. During sham feeding, the antrum exhibited transient phasic contractions in five out of six subjects. The duodenal motility index recorded for up to 30 min after the onset of the sham feeding was unchanged in five out of six subjects. We conclude that sham feeding consistently interrupted phase III of the duodenal MMC and induced antral contractions, but failed to provoke significant motor events in the duodenum.     

Human duodenal phase III migrating motor complex activity is predominantly antegrade, as revealed by high-resolution manometry and colour pressure plots.

Abstract Late phase III migrating motor complex activity has been said to be primarily retroperistaltic but has not been assessed with high resolution manometry or three-dimensional colour pressure plots (pressure/time/distance). Duodenal phase III was examined in healthy young volunteers (seven male, two female) with a 20-lumen assembly. With the most proximal sidehole in the distal antrum, after a 4.5-cm interval 18 sideholes at 1.5-cm intervals spanned the duodenum with a final sidehole 3 cm beyond. Fasting pressures were recorded until phase III occurred. Comparisons were made between proximal (P) and distal (D) duodenum during early (E) (first 0.5-1 min) and late (L) (last 0.5-1 min) phase III. With colour pressure analysis, 121 of 180 pressure wave (PW) sequences were purely antegrade, two purely retrograde and 57 bidirectional. Ten of fifty-seven bidirectional PW sequences were complex, branching to become two separate sequences. Bidirectional sequences occurred more frequently in late than early phase III (L 43 vs. E 14 of 57), but their occurrence did not differ between proximal and distal duodenum (P31 vs. D 24 of 57). Antegrade propagation velocity was faster in late compared with early phase III (L 28.50 vs. E 17.05 mm s(-1); P = 0.006), but did not differ between proximal and distal duodenum. Colour pressure analysis also indicated an intermittent segmental pattern to phase III, with each subject exhibiting a change in velocity or direction, or a relative failure of peristalsis somewhere along the duodenum during part of phase III. Duodenal phase III is not homogenous and, in contrast with previous studies, does not primarily constitute a retroperistaltic pump. Colour pressure analysis is useful in interpreting intraluminal pressure profiles and may improve the sensitivity and specificity of clinical studies.     

Intragastric acidification inhibits motilin-induced phase III activity in humans

In a randomized, placebo-controlled crossover design we studied the effect of gastric acidification on motilin-induced interdigestive antropyloroduodenal motility. Ten healthy volunteers participated in the study consisting of four experiments. Each experiment started after a spontaneous occurring phase III and consisted of intragastric infusion of either saline or acid (0.08 mol L(-1) HCl) for 90 min and intravenous infusion of either saline or motilin (4 pmol kg(-1) min(-1)) for 30 min. Antropyloroduodenal motility and pH were recorded continuously for 240 min. Reoccurrence of phase III was significantly (P < 0.05) earlier during intragastric saline-intravenous motilin infusion compared with control (intragastric saline-intravenous saline), 52 min (range 25-79) and 113 min (84-141) respectively. This effect was completely abolished during intragastric acid-intravenous motilin infusion, 112 min (82-142). The percentage of phase III of antral origin was significantly (P < 0.05) higher during intragastric saline-intravenous motilin infusion (90%) compared with control (30%). The mean area under the contraction (AUC) for phase II was significantly (P < 0.05) lower during intragastric saline-intravenous motilin infusion and intragastric acid-intravenous saline infusion compared with control. It is concluded that in humans intragastric acidification inhibits the effect of motilin on antroduodenal motility, decreases the AUC of antral phase II contractions and delays the occurrence of phase III of the migrating motor complex.     

Inhibition of the migrating motor complex by duodenal drainage in man

Abstract The effect of varying bile acid output on fasting small intestinal motility was investigated in healthy male volunteers. Biliary output was manipulated by jejunal infusion of isotonic mannitol, which resulted in increased output, and by prolonged drainage of duodenal contents, which resulted in decreased output. Intestinal motility was measured by manometric recordings performed at four levels in the proximal small intestine. A marker dilution technique was used to measure pancreatico-biliary output. There were three experimental groups: duodenal drainage, non-drainage and control. Both duodenal drainage and non-drainage groups underwent jejunal saline infusion, followed by mannitol infusion. The control group did not receive drainage or infusions. In the drainage group, 0.41 (0.13-0.68) activity fronts of the migrating motor complex (MMC) per hour were recorded during saline infusion, but only 0.06 (0-0.19) activity fronts per hour were observed during mannitol infusion. In the nondrainage group, 0.71 (0.61-0.81) activity fronts per hour were observed during saline infusion and 0.50 (0.18-0.82) activity fronts per hour were recorded during mannitol infusion. In the control group, 0.58 (0.33–0.84) activity fronts per hour were recorded during the first 4-h session and 0.58 (0.45-0.71) activity fronts per hour during the second session. There was no difference between the number of activity fronts per hour observed in the control group and those observed in the saline infusion of the drainage group. In contrast, there was a significant decrease in the number of activity fronts per hour in the drainage group during mannitol infusion, compared to both non-drainage group during mannitol infusion (P < 0.01) and controls (P < 0.05). In conclusion, decreased biliary output caused by duodenal drainage in combination with mannitol infusion is associated with inhibition of the cyclic activity of MMC in the proximal small intestine in man.     

Sonographic demonstration of human small intestinal migrating motor complex phase III

Background Migrating motor complex phase III (MMC phase III) of intestine is an important physiological mechanism traditionally recognized by myoelectric recordings or pressure tracings. Direct imaging is difficult and sonographic visualization in human has not been reported. Methods We have demonstrated this unique phenomenon in three patients who underwent abdominal sonographic examinations. Characteristic images were recorded by videotape and both spatial and temporal features were analyzed. Key Results Occurrences of multiple equally spaced, rhythmic intestinal contractions were observed. Parameters including wave frequency, propagation velocity, and duration of the events agreed with those of the well‐known phase III. The presence of distinct cyclic patterns observed in two and abolition by meal in the other patient further support our conclusion. Conclusions & Inferences We conclude that the migrating waves observed in our study represent the human MMC phase III. This unique finding in human subjects merits further investigation.     

High interdigestive and postprandial motilin levels in patients with the irritable bowel syndrome

Motilin shows cyclic variation with the different phases of the migrating motor complex (MMC). Altered motilin levels have been found in irritable bowel syndrome (IBS) patients, but in these studies motilin levels were analysed without the knowledge of the phases of MMC. We included 13 healthy controls (HC) and 24 patients with IBS [12 diarrhoea-predominant (IBS-D) and 12 constipation-predominant (IBS-C)]. We performed interdigestive and postprandial antroduodenojejunal manometry and blood samples for analysis of motilin were drawn. Group differences in plasma levels of motilin were analysed during mid-phase II, just before the start of phase III (pre-III), during phase I, immediately before the meal and 30 and 60 min after the 500 kcal mixed meal. Higher motilin levels were observed in IBS vs HC in both the interdigestive and postprandial periods (P < 0.05). No significant differences between IBS-C and IBS-D were observed. The cyclic variation of motilin during MMC and the meal response was similar in IBS and controls. IBS patients, irrespective of the predominant bowel habit, demonstrate higher motilin levels than HCs in all phases of the MMC and also after a meal. These findings may bear some pathophysiological importance in IBS and relate to the gastrointestinal dysmotility often seen in these patients.     

The migrating motor complex modulates intestinal motility response and rate of gastric emptying of caloric meals

Abstract The present study elucidates whether the phase of the migrating motor complex (MMC) present at the moment of food intake modulates postprandial motor response and rate of gastric emptying of caloric meals. Eight healthy male volunteers with a mean age of 26 years were examined twice. During water-perfused gastroduodenal manometry, a liquid meal with paracetamol added as a marker was orally administered during phase I and late phase II. Paracetamol appeared in serum 14.1 ± 3.8 min and 9.1 ± 4.0 (mean ± SD) min, respectively, after intake of the meal (P < 0.02). The area under the curve of s-paracetamol until 25 min after intake was 232 ± 169 μmoll_-1 min and 362 ± 130 (P < 0.05), respectively. When taken during late phase II, a phase III-like activity occurred within 2.1 ± 1.3 min in the duodenum, and was succeeded by quiescence. During phase I, the meal invariably initiated irregular contractions within 4 min. The phase of MMC during which a caloric meal is ingested modulates duodenal motor response and rate of gastric emptying during the initial postprandial period. Initial postprandial motor activity thus represents the combined effect of nutrient stimulation and the underlying enteric biorhythm as reflected by phase of MMC.     

Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach

In humans and dogs, it is known that motilin regulates phase III contractions of migrating motor complex (MMC) in the fasted state. In rats, however, motilin and its receptor have not been found, and administration of motilin failed to induce any phase III-like contractions. Ghrelin was discovered as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) from the rat stomach. Ghrelin promotes gastric premature phase III (phase III-like contractions) in the fasted state in rats. We hypothesized that endogenous ghrelin regulates spontaneous phase III-like contractions in rats. Strain gauge transducer was sutured on the antrum and a catheter was inserted into the jugular vein. We studied the effects of i.v. administration of ghrelin and a GHS-R antagonist on gastric phase III-like contractions in conscious rats. Plasma level of ghrelin was measured by a radioimmunoassay. Ghrelin augmented spontaneous phase III-like contractions and a GHS-R antagonist significantly attenuated the occurrence of spontaneous phase III-like contractions. During the phase I period, plasma ghrelin level increased to its peak then returned to basal level, subsequently phase III-like contractions were observed. These results suggest that endogenous ghrelin regulates gastric phase III-like contractions in rats.     

Human postprandial gastric emptying of indigestible solids can occur unrelated to antral phase III

According to animal experiments, postprandial gastric emptying of indigestible solids is mainly related to the antral phase III activity of the migrating motor complex. Gastric emptying of indigestible solids in humans has not been directly correlated to pressure recordings. The aim of the present study was to investigate the postprandial emptying pattern of indigestible solids in humans and its relation to fed and fasted antral motility. Ten healthy volunteers participated. After an overnight fast they had a standard breakfast. Two sizes of radiopaque markers (ROMs) were given with the test meal; ten cubes each of side measurement 1.5 mm and 3 mm, respectively. Emptying of the ROMs from the stomach was followed by fluoroscopy with simultaneous antral manometry. In six of the subjects, fasting antral manometry was performed on one day and on another day, the emptying of 7 mm cylindrical particles together with 3 mm cubes, in the absence of a gastric tube was recorded. All ROMs were emptied within 5 h (range 1.5-4.5 h). In all subjects, the smaller particles (1.5 mm) showed a slight, insignificant tendency to move from the stomach more rapidly than the larger (3 mm) particles. None of the subjects had an antral phase III before all ROMs were emptied from the stomach. Instead, the typical irregular postprandial pressure activity was present in all subjects until the emptying was completed. Furthermore, the highest postprandial motility index during the emptying study was far below the motility index during phase III, but comparable to the motility index during late phase II. Emptying of the 7 mm particles occurred significantly more slowly at 1.5-2.5 h, but otherwise was similar to the emptying of the smaller particles. There was no difference between emptying of the 3 mm cubes with or without the presence of the tube. Contrary to common opinion, gastric emptying of indigestible solids after a meal can occur unrelated to the antral phase III, at least up to a particle size of 3 mm and perhaps even 7 mm. These findings are of great importance for the evaluation of gastric emptying of indigestible solids, including the pharmacodynamics of orally administered drugs.     

Comparative analysis of phase III migrating motor complexes in stomach and small bowel using wireless motility capsule and antroduodenal manometry

Background Assessment of phase III MMC is often not performed due to the invasive nature of antroduodenal manometry used to detect it. The aim of the study was to evaluate the ability of wireless motility capsule (WMC) to detect phase III MMC and correlate it with the simultaneous measurements by antroduodenal manometry (ADM). Methods Eighteen patients underwent simultaneous ADM and WMC. MMCs were identified first on ADM and then correlated with WMC events occurring simultaneously. Frequency of contractions per min, AUC, MI, and criteria for amplitude thresholds of contractions representing MCCs on WMC tracings were defined. Key Results In 18 patients, a total of 29 MMCs were recorded by ADM. WMC detected 86% of MMC events measured by ADM. Hundred percent (10/10) of MMCs in stomach were detected by WMC, whereas 79% (15/19) of MMCs were detected in SB. The sensitivity and specificity of WMC high amplitude contractions to represent phase III MMC were 90% and 71.8% in the stomach; 73.7% and 84.7% in SB, respectively, and negative predictive value was 99.9% in both regions. Conclusions & Inferences Wireless motility capsule was able to detect the phase III MMCs as the high amplitude contractions with good fidelity. WMC does not detect the propagation of MMC. Using the pressure thresholds, WMC can detect high amplitude contraction representing phase III MMC with favorable sensitivity/specificity profile and 99.9% negative predictive value. This observation may have clinical significance, as the absence of high amplitude contractions recorded by WMC during fasting state suggests absence of MMCs.     

Phase III of the migrating motor complex: associated with endogenous xenin plasma peaks and induced by exogenous xenin

Xenin, a recently discovered peptide produced by specific endocrine cells of the duodenal mucosa, has shown exocrine, endocrine and motility effects in the gastroenteropancreatic system in animal experiments. The aim of the present investigation was to study the role of xenin in the regulation of duodenojejunal motility of humans. Twenty-nine healthy volunteers from the hospital staff gave informed consent to participate in this investigation. In 20 volunteers, we determined plasma concentrations of immunoreactive xenin at 15 min intervals over a mean time period of 8 h fasting and recorded the interdigestive motor activity of the duodenojejunum. In a double-blind randomized crossover study on other nine subjects, synthetic xenin in a dose of 4 pmol kg-1 min-1 or placebo was infused for 10 min intravenously in the interdigestive period and postprandially after a liquid meal. Duodenojejunal motility was recorded simultaneously. Predefined interdigestive xenin plasma peaks were found to be significantly associated with the phases III of the migrating motor complex. In the interdigestive period, xenin induced a premature phase III activity in each volunteer; this was followed by a second phase III in five out of nine subjects. In the postprandial state, xenin significantly increased contraction frequency and the percentage of aborally propagated contractions. These findings suggest a role of the peptide hormone xenin in modulating interdigestive and postprandial duodenojejunal motility in humans.     

High-resolution analysis of the duodenal interdigestive phase III in humans

To study the spatial organization of the propagating pressure waves of duodenal phase III, we performed fasting antroduodenal high-resolution manometry with a 16-channel catheter in 12 healthy subjects. The phase III pressure waves diverged in an anterograde and retrograde direction from the start site of each pressure wave. The pressure waves maintained this configuration as the activity front moved distally in the duodenum. The start site of the pressure waves moved gradually to a point approximately 12 cm (median) distal to the pylorus and remained at this point for about 40% of the phase III time before moving further distally. The length of retrograde pressure wave propagation increased to 6 cm (median) as the pressure wave origin moved aborally to a point 10-14 cm distal to the pylorus, and then decreased when the origin of pressure waves reached the distal end of the duodenum. Bidirectional pressure waves dominated in both retrograde and anterograde activity fronts. Three pressure-wave mechanisms behind the duodenal phase IV were observed. Isolated pyloric pressure waves were absent during late duodenal phase III retroperistalsis. Thus, a number of new features of the duodenal phase III-related motility were observed using high-temporospatial resolution recordings.     

Neurochemical mechanism of the gastrointestinal interdigestive migrating motor complex in rats with acute inflammatory stomach ache

The normal gastrointestinal interdigestive migrating motor complex cycle was interrupted, and paroxysmal contraction appeared after formaldehyde-induced stomach ache. Activities of nitric oxide synthase, acetylcholinesterase and vasoactive intestinal peptide neurons were significantly reduced, whereas activities of calcitonin gene-related peptide neurons were significantly increased in the pyloric sphincter muscular layer, myenteric nerve plexus and submucous nerve plexus. Electroacupuncture at Zusanli (ST36) suppressed paroxysmal contraction in rats with formaldehyde-induced stomach ache, and neurons in the enteric nervous system were normal. These results indicated that nitrergic neurons, cholinergic neurons, vasoactive intestinal peptide neurons and calcitonin gene-related peptide neurons in the enteric nervous system may be involved in changes to the gastrointestinal interdigestive migrating motor complex following stomach ache, and that electroacupuncture can regulate this process.     

Characteristic motor patterns of phase II and behaviour of phase III in the fed state

The motor pattern of the phase II of the migration motor complex (MMC) is poorly characterized and it remains to be determined whether it differs from the fed motor-pattern. Furthermore, discrepancy exists on the disruption of ongoing MMCs by feeding, and finally, the understanding of the behaviour of phase Ills during enteral nutrition is incomplete. Therefore, canine intestinal motility was studied after meal and during enteral infusion of nutrients (elemental diet, glucose, maltose, amino acids) or of hypertonic saline (300–1520 mosmol kg^?1). Motility of the proximal, mid- and distal jejunum was recorded with strain-gauge transducers. The motor patterns of the interdigestive phase II, after feeding and during enteral nutrition were analysed by a computer. Additionally, the disruption of the MMC by food and by enteral infusion of nutrients or hypertonic saline was investigated. The inter digestive phase II consisted of three different contractile patterns, clustered contractions, a mixed contractile pattern and non-migrating bursts of propagated contractions (NBPCs). NBPCs differed significantly from the phase III activity in several motility parameters and by the lack of aboral migration. Only small differences existed between the motor patterns of phase II and of the fed state, whereas the motor pattern induced by enteral infusion of an elemental diet differed significantly from that of phase II. Ongoing MMCs of the proximal jejunum often continued to migrate to the mid- and distal jejunum. During enteral infusion of nutrients or of hypertonic saline, phase Ills recurred. The migration of ongoing phase Ills and the recurrence of subsequent phase Ills decreased with increasing caloric or osmotic loads. The following conclusions were reached, (a) The phase II of the MMC is a complex motor-pattern. NBPCs represent a new contractile pattern, (b) The MMC is a characteristic feature of the empty gut. After meal and during enteral nutrition, phase Ills are usually suppressed but they can recur during the digestive period.     

Differential effects of motilin on interdigestive motility of the human gastric antrum, pylorus, small intestine and gallbladder

Motilin was infused in this study with the aim of examining refractory characteristics for motilin stimulation of antral phase III and fasting gallbladder emptying. Moreover, interdigestive pyloric and small intestinal motility from duodenum to ileum were studied, as these may be target organs for motilin. Eight fasting, healthy male volunteers received, on separate subsequent days, repeated infusions of 13leucine-motilin (8 pmol (kg min)(-1) for 5 min) or saline at 30 min after phase IIIs in the duodenum. Interdigestive motility of the antrum, pylorus, duodenum, jejunum and ileum was measured for maximum 10 h by using a 21-lumen perfused catheter. Gallbladder motility was measured by ultrasonography. Motilin infusions induced antral phase IIIs, but only after a preceding phase III of duodenal origin. Under this condition, time-interval to phase III at the duodenal recording site was 30 +/- 13 (SEM) min after motilin, compared with 79 +/- 14 min after saline (P < 0.01), and compared with 121 +/- 13 min for motilin infusion following an antral phase III (P < 0.001). Motilin did not affect small intestinal motility or isolated pyloric pressure waves (IPPWs). However, the number of IPPWs was significantly affected by the origin of the preceding phase III, irrespective of whether motilin or saline was infused. Gallbladder volume decreased significantly within 10 min after each motilin infusion. We conclude that this study clearly demonstrates differential regional effects of motilin. Motilin initiates antral phase IIIs, but stimulation is subject to a refractory period which is clearly prolonged after a preceding antral phase III. Motilin induced gallbladder emptying, however, is not subject to a refractory state. Small intestinal phase IIIs as well as pyloric IPPWs are not affected by motilin.     

Evaluation of the refractory period of the human migrating motor complex through induction of premature Phase III

We examined the refractory period of the migrating motor complex and the ability of somatostatin to increase the oscillation frequency of the complex through the initiation of premature phase HI activity. Fifteen normal human subjects were studied by means of a naso-intestinal motility probe and divided in three groups of five subjects each. After recording three spontaneous migrating motor complexes, somatostatin was infused at a time interval from the last spontaneous Phase III that corresponded to 10% (Group A), 20% (Group B) and 30% (Group C) of the previous mean cycle length. Eleven successive somatostatin infusions were given with the interval between each infusion being altered in a fashion designed to identify the refractory period of the MMC. The results show a spontaneous cycle length of 121.3 ± 15.8 min (mean ± SD). When given at 10% (12 min) of the previous cycle somatostatin did not elicit any response, when given at 20% (24 min) of the cycle somatostatin induced a premature Phase III activity in three of five subjects; when given at 30% (36 min) of the cycle somatostatin induced a premature Phase III in all five subjects examined. Each somatostatin infusion was associated with the onset of a premature Phase III activity in 50% of the trials when the time interval was 20% of the ideal cycle (24 ± 4 min). When the time interval was increased to 30% of the ideal cycle a premature Phase III could be recorded after each somatostatin infusion in all trials. Motilin and pancreatic polypeptide plasma levels were significantly lowered by somatostatin. It is concluded that the migrating motor complex of the human gastrointestinal tract shows an absolute and a relative refractory state. Repetitive infusions of somatostatin for short periods may increase the occurrence of Phase III activity up to four-fold.     

Endogenous nitric oxide release modulates the direction and frequency of colonic migrating motor complexes in the isolated mouse colon

Spontaneous colonic migrating motor complexes (CMMCs) were recorded from circular muscle at three sites along the isolated mouse colon. The interval between CMMCs was decreased from approximately 3 min in control solution, by approximately 55% in a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine (L-NNA; 100 micromol L-1). This was associated with a shift in migration direction of CMMCs, such that CMMCs migrated in an oral direction. Application of the endogenous substrate for NOS, L-arginine, at a low concentration used to mimic plasma concentration (134 micromol L-1), or a high concentration (5 mmol L-1) suppressed CMMCs (for at least 15 min) which were replaced by high frequency (10-15 min-1), short duration (half width approximately 1.5 s) contractions of variable amplitudes (largest in the proximal region) until CMMCs resumed. CMMCs remained in the presence of D-arginine (134 micromol L-1 and 5 mmol L-1). Apamin (250 nmol L-1) did not alter the interval between CMMCs, however, additional nonmigrating contractions were observed between the CMMCs in the distal region. In addition to its effects on smooth muscle tone, NO, but not apamin-sensitive channels, plays an important role in suppressing the frequency of migrating contractions in the isolated mouse colon. Consideration should be given to the inclusion of L-arginine, in in vitro experiments where there may be spontaneous activity in NOS containing neurones.